FI78697B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA BENZISOTIAZOL- OCH BENZISOXAZOLPIPERAZINDERIVAT. - Google Patents

Description

1 73697

This invention relates generally to heterocyclic compounds useful as medicaments. In particular, the invention relates to a process for the preparation of novel 1,4-disubstituted piperazine derivatives in which one substituent is 1,2-benzothiazol-3-yl or 1,2-10 benzisoxazol-3-yl and the other is heterocyclic (linked via an alkylene chain) or butyrophenone. (and the corresponding carbinol) radical represented by the formulas: 15 ° \ / \ "azaspiro / 4,5-decanedione" 20-0 1 - {\ / '"R1, R2-dialkylglutarimide" o 25

: O

: r <I n_ "thiazolidinedione" 30 ° ✓Λ o \ _ / S "spirocyclopentyl-2,4- 'thiazolidinedione" N-

O

35 «- <2 78697

O

/ = λ II

** "\ Λ /) C (CI ^)" butyrophenone "

5 ° H

F- / Λ-CH- and> "butyrophenone-CH 'carbinol" 10

U.S. Patent Nos. 3,398,151 and 3,717,634 to Wu and separately to the corresponding publications of Wu et al., J. Med. Chem. 12, (1969), ss. 876-881 and 15, (1972), p. Nos. 447 to 479 disclose a variety of psychotropic azaspiro / 4,5-decanedione dialkylglucar-imide compounds of formula (1) R1 -.0 20 XN-alkylene-n NB (1) H ^ 0 V_, Wherein R and R are alkylenes or joined together to form a group - (CH2) 4- or - (CH2) 5- and B represents, inter alia, phenyl and various heterocyclic groups (all optionally substituents):

r = r \ N = \ N

Ai Ai Aj

U.S. Patent No. 4,182,763 to Casten et al. Relates to the use of compound (4), referred to in the biological literature as buspirone, as an analgesic.

3 73697 Υ ^ -ίαψ, -ιΓΛ - (_ / '-4' - 'Ν - = / Ο 5

Benica et al. describe in J. Am. Pharmaceutical Association, (1950), ss. 451-456 3,3-dialkyl-2-glutarimides having C 1-4 alkyl and R is hydrogen or C 1-4 alkyl represented by formula (3) and mention that the compounds did not have a significant physiological effect.

CH3, 0 ΝΤ'.ν 20 Thiazolidinediones are known in the art. For example, Jones et al., J. Chem. Soc., London (1946), ss.

91-92, discuss 5,5-dialkyl-2,4-thiazolidinedione-barbituric acid analogs, and show that 5-spiro-cyclohexyl-2,4-thiazolidinedione (4) causes anesthesia and analgesia in mice.

-Q-R °

30 S NH

ν 'o

Various types of 1,4-35 substituted piperazine derivatives are also known in the art and are described in the following references.

4,73697 GB 2,023,594A discloses 1- (R-alkyl) -4- (3-trifluoromethylthiophenyl) piperazines useful in the treatment of anxiety and depression having the general formula (5) 5- (CH_) - t / ^ NO i - SCF0 (5) 2 n 3 10 where n is 1 to 3 and R represents, inter alia, heterocyclic groups such as /, CH2 »m, N-O 0 where m is 0 or 1 and X is -S-, -O-, imino, alkylimino or methylene.

Rojsner et al., Collect. Czech. Chem. Commun.

20 40 (4), (1975), p. 1218-1230 disclose, inter alia, butyrophenone derivatives of formula (6) as part of a psychotropic structure-activity relationship study.

25 Γ - ^^ £ ηοη2) 3-Ν ^ Ν - <^ Λ (6)

None of the above references discloses 1,2-benzisothiazole or 1,2-benzisoxazole-piperazine derivatives prepared according to the present invention.

The novel compounds of the invention are piperazinyl derivatives having antipsychotic properties and

35 of formula I

5 73697 R-N N —r— \ / H 1

> - / n JJ A

\ y 'X z 5 where R is a group of formula X. -W R1 \ T <0 -X ^ <<CH2> nn / ^ - i <CH2> n 0 0 (a) (b) 15 N- (CH-) - N_ (CH2) n "\ / 2 n / zn SCS" "\ 20 \% (o) (d) 1

O or OH

C 1-4 → 3- (3-) -CH- (CH 2) 3-30 (e) (f) wherein n is 3 or 4, R 1 and R 2 are independently alkyl of 1 to 4 carbon atoms, Y is oxygen or sulfur, Z is hydrogen or halogen, 673697 or pharmaceutically acceptable non-toxic acid addition salts thereof.

As used herein, halogen means fluorine, iodine and preferably chlorine and bromine.

Pharmaceutically acceptable acid addition salts prepared according to the invention are those in which the anion does not increase the activity and as such are pharmacologically equivalent to the bases of the formula I. They are generally considered to be the primary compounds suitable for pharmaceutical use. In some cases, they have physical properties that make them more desirable in a pharmaceutical combination, such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation, and miscibility with other ingredients. The salts are prepared in the usual manner by mixing a base of formula I with a selected acid, preferably by carrying out the combination in solution using an excess of commonly used inert solvents such as water, ether, benzene, ethanol, ethyl acetate and preferably acetonitrile. They can also be prepared by an exchange reaction or by treatment with an ion exchange resin under conditions in which the anion of a salt of a compound of formula I is replaced by another anion under conditions which allow the desired compounds to be separated, such as by doping or solvent extraction or eluting with an ion exchange resin. Pharmaceutically acceptable acids suitable for the formation of salts of the compounds of formula I include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, cinnamic acid, mandelic acid, limic acid, phosphoric acid, nitric acid, nitric acid, nitric acid,

7 78697

Compounds of formula I are prepared according to the invention such that A) for the preparation of compounds of formula I wherein R is as defined above in formula (a), (b), (c) · or (d)

5, an imidoyl compound of formula II

imide-A II

wherein A is - (Cl 2) -X, wherein n is as defined above and X 10 is an acid residue of a reactive ester group, and the imide is a group of formula

0 R, /.O

- DC- # o * o (a ') (b1): 20 j- ^ ° N- or N- s ~ i0 s —4

0 O

25 <c ') <d')

wherein R 1 and R 2 are as defined above are reacted with a compound of formula III

30 / ~ ^ / s.

HN N “Tj- <Vi

\ _ / Il I III

β 78697 wherein Y and Z are as defined above, in an inert reaction medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or B) to prepare compounds of formula I,

wherein R is a group of formula (a), (b), (c) or (d) as defined above, an imidoyl compound of formula IV

imide-M IV

Wherein M is an alkali metal salt and the imide is a group of formula (a '), (t »1), (c1) or (d1) as defined above, is reacted with a compound of formula V or V' (CH2 »n-" N- [| - [j ^ l 20 or X "V ^ N i-

ΊΓ1JL

Wherein n, X, Y and Z are as defined above, in an inert reaction medium at a suitable temperature for a time sufficient to form a compound of formula I or alternatively, without prior formation of an alkali metal salt of formula IV, formula (a1), (b '), (c') or (d ') reacting the corresponding free imide compound with a compound of formula V or V in an inert reaction medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or 9 73697

C) for the preparation of compounds of formula I wherein R is a group of formula (a), (b), (c) or (d) as defined above, a compound of formula VI

5 _

imide- (CH_) -N NH VI

n \ /

Wherein the imide is a group of formula (a '), (b1), (c') or (d1) as defined above and n is as defined above, is reacted with a compound of formula VII

halo-1, - wherein halo is halogen and Y and Z are as defined above, in an inert reaction medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or D) to prepare compounds of formula I wherein R is as defined above a group according to (a), (b), (c) or: (d), an anhydride of formula VIIIa, 25 VHIb, Ville or VHId do '';> q · 30 O R2 \

O

File Vlllb _j / \ _ j> 35 \ V / - \ I P tai o s- ~ s, s — 4

υ O

VHIc VHId 10 ΊΟ con i o u s /

wherein and R e are as defined above are reacted with a compound of formula IX

5

H2N- | cVn- {3 ~ rr J01 IX

z 10 wherein n, Y and Z are as defined above, in an inert reaction solvent for a time sufficient at a suitable temperature to form a compound of formula I, or

E) for the preparation of compounds of formula I wherein R is a group of formula (e) or (f) as defined above, a compound of formula III

wherein Y and Z are as defined above, are alkylated with a compound of formula X.

: 25: r ~ \ r = \? x - <CH 2 »3-X 1 2 3 4 5 6 wherein X is as defined above, in an inert solvent to give a compound of formula I wherein R is a group of formula 3 (e), and the resulting compound is reduced as desired. to a compound of formula I wherein R is a group of formula 5 (f), 6 and if desired converting a compound of formula I obtained by Method A, B, C, D or E to a pharmaceutically acceptable non-toxic acid addition salt thereof.

11 73697

In processes A, B and E, the acid residue X of the reactive ester group is, for example, chloride, bromide, iodine, fluoride, sulphate, phosphate, tosylate or mesylate, in process B in formula V primarily bromine, chlorine or iodine, in process E primarily chlorine it is bromine.

In Method B, the alkali metal salt M is, for example, sodium, potassium or lithium.

The above general embodiments of methods A, B and C 10 form a uniform process for the preparation of compounds of formula I wherein R is a radical (a), (b), (c) or (d) as defined above, and the process comprises alkylating a compound of formula III, IV or A compound of formula VI with a suitable alkylating compound of formula II, V, V or VII in a reaction inert solvent.

Methods A and C are conveniently performed under the reaction conditions used to prepare tertiary amines by alkylation of secondary amines. Thus, compounds of formula I wherein R is radical (a), (b), (c) or (d) are obtained by reacting the appropriate intermediates in an inert reaction medium at temperatures between about 50 ° C and about 200 ° C in the presence of a base, suitable for use as an acid scavenger. Useful inorganic and organic acid-binding bases are tertiary amines, alkali and alkaline earth metal carbonates, bicarbonates or hydrides, with sodium carbonate and potassium carbonate being particularly preferred. Throughout this specification and claims, the term "inert reaction medium" means any protic or aprotic solvent or diluent which does not participate in a substantial amount in the reaction. In this regard, acetonitrile is a particularly preferred solvent, whereby the reaction is conveniently carried out at boiling temperature. These compounds are obtained in satisfactory yields with reaction times of about 2-24 hours. The compounds of formula I can be purified by crystallization methods from common solvent media such as acetonitrile, isopropanol, methanol, ethanol and the like, and by other conventional methods such as chromatography on a silica gel column using silica gel and ethanol and chloroform as eluent. 5 mixtures.

Process B describes a variation of the uniform process of this invention for the preparation of compounds of formula I wherein R is a radical (a), (b), (c) or (d), which process comprises alkylating an alkali metal salt of an imide compound of formula IV. This reaction is carried out using standard laboratory methods, such as those described for the alkylation step of the Gabriel synthesis in S. Gabriel, Ber.

20 (1887), p. 2224. In this case, the reagents are compounded, for example, in an inert reaction medium at temperatures in the range from 50 to 200 ° C. Preferred solvents for carrying out the reaction are toluene and skylene, although other solvents which do not adversely affect the reaction or the reactants may be used. Useful solvents such as dioxane, benzene, dimethylformamide, acetone, acetonitrile, n-butanol and the like are useful in this regard. In general, alkali metal salts IV are prepared by treating the corresponding imide precursor with an alkali metal hydride such as sodium hydride; an alkali alcoholate such as sodium methylate; alkali. an amide such as sodium amide; an alkali base such as sodium hydroxide and potassium hydroxide; with an alkali carbonate such as sodium carbonate or potassium carbonate in a suitable solvent. Prior formation of the alkali metal salts of formula IV is not necessary and the imide precursor and piperazinyl alkylating agent (V or V) may be conveniently combined in an inert reaction medium with a base, preferably in the presence of sodium or potassium carbonate.

The pi-35-perazinyl-benzisothiazole and benzisoxazole compounds of formula III used in Method E are obtained by reacting 3-chloro-6-Z1,2-benzisothiazole or 3-chloro-6-Z1,2-benzisoxazole with an excess of piperazine used in excess. thermal i3 73697 mode. For example, 3-chloro-1,2-benzothiazole starting material is prepared by treating 1,2-benzothiazol-3 (2H) one with phosphorus pentachloride at 100-140 ° C for 4 hours. A similar conversion of 1,2-benzisoxazol-3-one to 3-chloro-1,2-benzisoxazole is performed with a phosphorus oxychloride / triethylamine mixture according to the method of H. Boshagen, Ber. 10 (1967), p. 3326.

The compounds 10 prepared in accordance with this invention are useful pharmacological agents having psychotropic properties. In this respect, they have a selective effect on the central nervous system in non-toxic doses and are of particular interest as anti-stressors (antipsychotics). Like other known antipsychotics, the compounds of formula I elicit certain reactions in the context of standard pharmacological in vivo and in vitro test methods which are known to be well correlated with the relief of human anxiety and the symptoms of acute chronic psychosis. The following describes conventional in vivo experimental procedures used to classify and distinguish a psychotropic substance from a non-specific CNS depressant and to determine potential side effect tendencies (e.g., cataleptic activity). In the latter relationship, the class of antipsychotics is known to cause sedative and extrapyramidyl reactions such as sudden circulatory muscle disorders, fear of sitting, tremor paralysis, slow movement disorders, and involuntary nervous system effects.

14 78697 Behavioral Test Reference Indirect Avoidance Reaction Albert, Pharmacologist, 4, Interruption (CAR) (1962), p. 152; Wu et al., J. Med. Chem. 12, (1969), 5 p. 876 - 881

Catalepsy Costall et al., Psychopachrmacologia, 34 (1974), p. 233 - 241; Berkson, J., Amer. Statist. Assoc. 48, 10 (1953), p. 565 - 599

Defensive mouse Tedeshi et al., J. Pharma col. Expt. Therap. 125, (1959), p. 28

Rotating rod Kinnard et al., J. Pharma- 15 col. Expt. Therap. 121, (1957), p. 353

Apomorphine stereotype Janssen et al., Arzneimitel-Forsch. 17, (1966), pp. 841 20

To further demonstrate the psychotropic activity and specificity of the compounds of this invention, an in vitro central nervous system respiratory binding methodology known in the art can be used. Certain compounds (commonly referred to as ligands) have been identified that bind primarily to high-affinity brain tissue sites that have to do with psychotropic activity or potential side effects. Inhibition of the binding of a radiolabeled ligand to such specific high-affinity sites is considered a measure of the ability of a compound to affect the corresponding central nervous system function or to cause side effects in vivo. This premise has been utilized in the following assays, which are presented by way of example.

15 73697

Receptor Binding Assay_ Reference

Dopamine Burt et al., Molec. Pharma col., 12 (1976), pp. 800; 5 Science 196, (1977), p.326;

Creece et al .; Science, 192, (1976), p. 481

Cholin action Yamamura et al., Proc. Natl.

causative agent Acad. Sci. USA 71, (1974) p.

10 1725

Qi receptor Crews et al., Science 202, (1978), p. 322; Rosenblatt et al., Brain Res. 160 (1979), pp. 186; U'Prichard et al., 15 Science 199 (1978), p. 197; U'Prichard et al., Molec. Pharmacol. 13, (1977), p. 454 Serotonin type 2 Peroutka and Snyder, Molec.

Pharmacol. 16, (1979), pp. 687 20

In accordance with the pharmacological profile found in the above experiments, the compounds of formula I according to the invention have a promising antipsychotic activity in that they are relatively effective in oral CAR experiments with ED 2 values <100 mg body weight. per kilogram and IC50Q-3 values <1000 nanomolan in the H-spiperonipipamine receptor binding assay. Activity in the CAR assay and spiperone assay is considered to predict anticipatory efficacy of an-30 in humans. With respect to the selective antipsychotic effect, the preferred compounds of formula I have a significant dopamine receptor binding effect and cause interruption in the rat CAR test at catalytically active doses.

is 73697

A particularly preferred compound in this regard is 8- [α- β- (1,2-benzoisothiazol-3-yl) -1-piperazinyl] butyl} -8-azaspiro [4,5] decane-7,9-dione , which has a relatively weak cataleptogenic effect in rats at a dose about 8 times the CAR dose, suggesting minimal efficacy for extrapyramidal side effects.

As previously mentioned, the compounds of the invention have psychotropic properties which make them particularly suitable for use as antipsychotics. Thus, they can be used to ameliorate a psychotic condition in a mammal in need of such treatment. In this case, the mammal is systemically administered an effective dose of about 0.01 to 40 mg per kilogram of body weight of the compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

The term systemic administration as used herein means oral, anal, or Parente-20 administration (i.e., intramuscular, intravenous, or subcutaneous). It will generally be appreciated that when a compound of formula I is administered orally (which is the preferred route), a greater amount of active ingredient is required to produce the same effect as when administered parenterally. In accordance with good clinical practice, these compounds are administered primarily at a concentration that produces potent antipsychotic effects without causing any deleterious or unpleasant side effects.

For therapeutic purposes, these compounds are usually administered as pharmaceutical compositions comprising an antipsychotically effective amount of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. Preferred additions are pharmaceutical compositions containing from about 1 to about 500 mg of active ingredient per dosage unit. They are in the form of conventional preparations, such as tablets, lozenges, capsules, powders, aqueous or oleaginous suspensions, syrups, alixirs or aqueous solutions.

Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), excipients (e.g. lactose, sugar, corn starch, calcium phosphate). sorbitol or glycine), glidants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulphate). Solutions or suspensions of a compound of formula I in conventional pharmaceutical media are used in the preparation of parenteral compositions such as an aqueous solution for intravenous injection or a suspension for intramuscular injection. Compositions having the desired brightness, stability and suitability for parenteral use are obtained by dissolving 0.1 to 10% by weight of the active compound in water or a medium consisting of a polyhydric aliphatic alcohol such as Glycerol, propylene glycol or polyethylene glycols or their mixtures. Polyethylene glycols are a mixture of non-volatile, usually liquid, polyethylene glycols that are soluble in both water and organic liquids and have molecular weights between about 200 and 1500.

The following examples illustrate the invention in more detail.

18 78 697

Example 1 3- (1-Piperazinyl) -1,2-benzisothiazole

O r O

A mixture of 3-chloro-1,2-benzisothiazole 10 (37.8 g, 0.235 moles) and piperazine (304.2 g, 3.53 moles) is heated under an atmosphere of argon for 20 hours at 120 ° C under seal. reactor. The reaction mixture is dissolved in 2 liters of water and the aqueous solution is repeatedly extracted with methylene chloride. The extracts are combined, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was dissolved in ether, filtered and evaporated to dryness in vacuo to give 24.4 g (47%) of 3- (1-piperazinyl) -1,2-benzisothiazole, free base, as a viscous oil.

A sample of the free base is converted to the hydrochloride salt in ether with ethanolic hydrogen chloride solution and crystallized from methanol-ethanol to give analytically pure 3- (1-piperazinyl) -1,2-benzisothiazole hydrochloride, m.p. 280 ° C (dec.).

Analysis for C 12 H 12 N 3 S 3 HCl: Calculated: C 51.66 H 5.52 N 16.43 Found: C 51.34 H 5.46 N 16.16 19 78697

Example 2 3- (1-Piperazinyl) -1,2-benzoxazole 5 H-N-r-10

A mixture of 3-chloro-1,2-benzisoxazole (19.6 g, 0.128 mol) and piperazine (110 g, 1.28 mol) is heated for 20 hours at 120 ° C in a closed reactor. The reaction mixture is diluted with water and water. the mixture is repeatedly extracted with methylene chloride. The extracts are combined, dried over magnesium sulphate and evaporated to dryness in vacuo to give 21.2 g (82% yield) of 3- (1-piperazinyl) -1,2-benzisoxazole as the free base.

A sample of the free base is converted to the hydrochloride salt and crystallized from methanol-ethanol to give analytically pure 3- (1-piperazinyl) -1,2-benzisoxazole hydrochloride, m.p. 326 ° C (dec.).

Analysis for C 11 H 13 N 3 O · HCl: Calculated: C 55.12 H 5.89 N 17.54 Found: C 55.25 H 5.82 N 17.53 20 73697

Example 3 8- / 5- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,5] decane-7,9-dione 10

Method A. A mixture of 3- (1-piperazinyl) -1,2-benzisothiazole (24.3 g, 0.11 mol) and 8- (4-bromobutyl) -8-azaspiro [4.5] decane-7,9-dione (33.5 g, 0.11 mol), anhydrous potassium carbonate (32.4 g, 0.23 mol) and potassium iodide (3.9 g, 0.023 mol) per liter of acetonitrile, stir and heated to reflux for 20 hours, the reaction mixture is filtered, evaporated to dryness in vacuo and the residue is dissolved in 350 ml of chloroform which is filtered and evaporated to dryness in vacuo. The residue is triturated with ether, kept cold and the solid formed is collected. This material is crystallized from acetonitrile (using activated charcoal gives a first batch, 25.1 g, m.p. 120-124 ° C and a second batch, 6.0 g, m.p. 123-126 ° C) in a total yield of 31.1 g. (yield 64%) of the free base form of the title compound. Crystallization from acetonitrile gives analytically pure 8- [4 - [- (1,2-benzoisothiazol-3-yl) -1-piperazinyl] butyl] -α-azaspiro [4,7] decane-7,9-dione,

30 sp. 124-126 ° C

Analysis for C 24 H 32 N 4 O 2 S: Calculated: C 65.42 H 7.32 N 12.72 Found: C 65.45 H 7.31 N 12.75 NMR (CDCl 3): 1.60 (12H, m), 2.57 (4H, s), 2.62 (6H, m), 3.54 (4H, m), 3.79 (2H, m), 7.34 (2H, m), 7.81 ( 2H, m).

2i 78697

An ethanolic solution of hydrogen chloride (12.3 mL, 5.7-n) is added to a suspension of the free base (31 g) in hot isopropanol. The resulting solution is cooled and the precipitate formed is collected and dried in vacuo at 80 ° C to give 29.6 g of 8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl]. N-azaspiro [3,7] decane-7,9-dione hydrochloride, mp 219-220 ° C.

Analysis for C 24 H 32 N 4 O 2 S 2 HCl: 10 Calculated: C 60.43 H 6.98 N 11.75 Found: C 60.57 H. 6.98 N 11.75 NMR (DMSO-d 6): 1.55 (12H, m), 2.64 (4H, s), 3.40 (10H, m), 4.05 (2H, d, 12.0Hz), 7.50 (2H, m), 12.5 ( 1H, bs).

A sample of the free base product is crystallized from acetonitrile with ethanolic hydrogen chloride to give 8- / 5- [5- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,] 7decan-7. , 9-dione dihydrochloride dihydrate, m.p. 118-120 ° C.

Analysis for 2HCl.2H2O: Calculated: C 52.45 H 6.97 N, 10.20 Found: C 52.68 H 6.91 N, 10.29 NMR (DMSO-d 6): 1.55 (12H, m), 2.64 (4H, s), 3.14 (4H, m), 3.58 (6H, m), 4.06 (2H, d, 12.0Hz), 5.48 (4H, s), ), 7.50 (2H, m), 8.10 (2H, m), 11.60 (1H, bs).

Method B. A mixture of 3- (1-piperazinyl) -1,2-benzisothiazole (5.0 g, 0.0228 mol) 1,4-dibromobutane (9.8 g, 0.0456 mol) ) and finely ground anhydrous potassium carbonate (7.9 g 0.057 mol) in 100 ml of ethanol are stirred and boiled for 16 hours. The cooled reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residual solid is heated to boiling with 70 ml of isopropanol and filtered. Concentration of the filtrate to half its volume and cooling gives 5.58 g (yield 69.1%) of 22,73697 8- (1,2-benzisothiazol-3-yl) -8-aza-5-azoniaspiro [3,5] acane -bromidia, m.p. 246.5 - 253 ° C.

Analysis for C 15 H 20 ClN 3 S.1 / 4H 2 O: Calculated: C 50.21 H 5.76 N 11.71 H 2 O 1.26 Found: C 50.04 H 5.68 N 11.6 H 2 O 1.50

A mixture of 3,3-tetramethyleneglutarimide (2.52 g, 0.0151 mol), 8- (1,2-benzisothiazol-3-yl) -8-aza-5-azonia-spiro [5,5] decane bromide (5, 34 g, 0.0151 mol) and ground potassium carbonate (2.4 g, 0.0173 mol-10) in 125 ml of toluene, boil and stir for 24 hours, filter and evaporate to dryness. The residue is dissolved in boiling toluene and diluted with hot heptane. The hot solution was treated with charcoal, filtered and cooled to give 4.46 g (67.2% yield) of a solid, m.p. 109.5-120 ° C. Crystallization from methanol gives the free 8- [5- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4.57] decane-7,9-dione base, m.p. 127.5-130 ° C.

Example 4 8- {3- [3- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,5] decane-7,9-dione] tjO 1 2 3 4 5 6

By reacting 8- (4-bromobutyl) -8-azaspiro [3,5 / 2] decane-7,9-dione and 3- (1-piperazinyl) -1,2-benz-3-isoxazole according to the method of Example 3 4 and crystallization of the free base from isopropanol gives 8- [3- [4- (1,2-benzisoxazol-3-yl) -1-6 piperazinyl] -butyl] -8-azaspiro / 3,57-decane in 40% yield. 7.9-23 78697 dione hemihydrate. mp. 96-98 ° C.

Analysis for C 24 H 32 N 4 O 3 · 1 / 2h 2 O: Calculated: C 66.49 H 2, 68 N 12.93 H 2 O 2.08 Found: C 66.59 H 7.59 N 12.87 H 2 O 2.38 δ NMR (CDCl 3 ): 1.55 (12H, m), 2.41 (2H, m), 2.57 (4H, s), 2.60 (4H, m), 3.57 (4H, m), 3.89 (2H, m), 7.15 (1H, m), 7.41 (2H, m), 7.66 (1H, d), 8.0 Hz).

Example 5 3- [3- / 4- (1,2-Benzisothiazol-3-yl) -1-piperazin-10-yl] butyl] -2,4-thiazolidinedione

O

(a) 2,4-Tlazolidinedione sodium salt 2,4-Thiazolidinedione (11.71 g, 0.1 mol) and 100 ml of 0.1 N sodium hydroxide (0.1 mol) are mixed and, if necessary, heated to give a solution. to obtain. Concentration of the basic solution in vacuo gives a semi-solid which is repeatedly triturated with acetone and removed by removal of the solvent in vacuo to give a crystalline solid. This material was collected, washed with acetone and dried at 60 ° C under vacuum to give 15.1 g (95% yield) of the sodium salt of 2,4-thiazolidinedione, m.p. 225 ° C (dec.).

(B) 3- (4-Bromobutyl) -2,4-thiazolidinedione The 2,4-thiazolidinedione sodium salt (13.91 g 0.1 mol) is added to a solution of 1,4-dibromobutane (66.7 g). .3 moles) in 500 ml of dry dimethylformamide. After stirring at room temperature for 35 hours, the resulting clear solution is concentrated in vacuo and the residue is dissolved in chloroform, filtered and evaporated in vacuo to a tan oil. Distillation of the oil gives 20.62 g (81% yield) of 3- (4-bromobutyl) -2,4-thiazolidinedione, b.p. 105-115 ° C / 5 0.02 mmHg.

(c) 3- [3- [3- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione dihydrochloride By administering 3- (4-bromobutyl) -2.4 -thiazolidinedione was reacted with 3- (1-piperazinyl) -1,2-benzisothiazole according to the procedure of Example 3 and the free base was converted to the hydrochloride salt in acetonitrile to give 3- [3- / 3- (1,2-benzisothiazole) in 43% yield. 3-yl) -1-Piperazinyl-7-butyl] -2,4-thiazolidinedione dihydrochloride, m.p. 200-202 ° C, from acetonitrile.

Analysis for C 18 H 22 N 4 O 2 • 2 ': Calculated: C 46.65 H 5.22 N 12.09 Found: C 46.35 H 5.31 N 13.10 NMR (DMSO-d 6): 1.70 (4H , m), 3.16 (4H, m), 3.54 (6H, m), 4.06 (2H, d, 12.0Hz), 4.21 (2H, s), 7.51 (2H, m), δ 8.10 (2H, m), 11.55 (1H, bs).

, Example 6 3- [3- [3- (1,2-Benzoxoxazol-3-yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione 25 0 1 2 3 4 5 6 2

Reaction of 3- (4-bromobutyl) -2,4-thiazolidine 3 dione with 3- (1-piperazinyl) -1,2-benzisoxazole 4 according to the method of Example 3 gives 3- (T [4- (1,2-benzisoxazol-3-yl) -1-6 piperazinyl] butyl] -2,4-thiazolidinedione hydrate, m.p. 104.5-106.6 ° C, from methanol.

25 78697

Analysis for C 29 H 22 N 4 O 3 S · 1/41 ^ 0: Calculated: C 57.06 H 5.99 N 14.79 H 2 O 1.19 Found: C 57.17 H 5.98 N 14.78 H 2 O 1.28 NMR ( CDCl 3): 1.64 (4H, m), 2.42 (2H, t, 6.6Hz), 2.61 (4H, m), δ 3.58 (6H, m), 3.92 (2H, s), 7.42 (4 H, m).

Example 7 8- [4- [3- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -butyl] -6-thia-8-azaspiro) / 4,4 / nonan-7 , 9-dione 10 ° X (a) 5-Spirocyclopentyl-2,4-thiazolidinedione sodium salt 5-Spirocyclopentyl-2,4-thiazolidinedione obtained according to Jones et al., 20 (1.71 g, 0.01 mol) and 10 ml of 1.0 N sodium hydroxide (0.01 mol) are mixed together and heated if necessary to obtain a solution. Concentration of the basic solution, repeated trituration with acetone and removal of the solvent in vacuo gave 1.66 g (86% yield) of the sodium salt of 5-spirocyclopentyl-2,4-thiazolidinedione, m.p. 243-245 ° C.

(b) 3- (4-Bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione The sodium salt of 5-spirocyclopentyl-2,4-thiazolidinedione (3.83 g, 0.019 mol) in 180 ml of dimethylformamide is slowly added 1.4 -dibromobutane (12.84 g, 0.059 mol) in 20 ral of dimethylformamide. The mixture is stirred at room temperature for 16 hours and then evaporated to dryness in vacuo. The residue was dissolved in chloroform, filtered and the filtrate was concentrated and distilled to give 4.96 g (85% yield) of 3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione, b.p. 122-126 ° C / 0.04 nutiHg.

(c) Hydrochloride hydrate of the title product An-5 by reacting 3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione with 3- (1-piperazinyl) -1,2-benzisothiazole and changing the free base to the hydrochloride salt according to the method of Example 3 is obtained in 84% yield 8 - [[4- [3- (1,2-benzisothiazol-3-yl) -10'-piperazinyl] butyl] -6-thia-8-azaspiro [4], 47-nonane-7,9-dione hydrochloride hydrate, mp 214 ° C, from ethanol Analysis calculated for the compound: C 54.72 H 6 10 N 11 60 H 2 O 0.37 found: C 54.40 H 6 22 N 11 40 1 H 0.46 NMR (DMSO-d 6): 1.74 (8H, m), 2.20 (4H, m), 3.15 (4H, m), 3.52 (6H, m), 4, Δ (2H, d, 12.0Hz), 7.49 (2H, m), 8.09 (2H, m), 11.60 (1H, bs).

Example 8 8- / 4- [4- (1,2-Benzisoxazol-3-yl) -1-Piper-20-azinyl] butyl] -6-thia-8-azaspiro [4.4] nonane-7,9- dione

Reaction of 3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione with 3- (1-piperazinyl) -1,2-benzisoxazole and conversion of the free base to the hydrochloride salt according to the procedure of Example 3 gives 88%: yielding 8- [4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] butyl] -6-thia-8-azaspiro [1,4] nonane-35,7,9-dione- hydrochloride hydrate, m.p. 212-214 ° C, from isopropanol.

2? 78697

Analysis for C 22 H 28 N 4 O 3 S * HCl * ° 75H 2 O: Calculated: C 55.22 H 6.42 N 11.71 H 2 O 2.82 Found: C 54.92 H 6.23 N 11.51 H 2 O 2.42 NMR ( DMSO-d 6): 1.75 (8H, m), 2.18 (4H, m), 3.34 δ (10H, m), 4.07 (2H, d, 12.0 Hz), 7.44 ( 3H, m), 7.98 (1H, m), 11.20 (1H, bs).

Example 9 1- [4- / 4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -4-methyl-4-propyl-2,6-10 piperidininedlon chl 2 CH 3 CH 2 CH 2 O ( a) N- (4-Bromobutyl) -3-methyl-3-n-propyl-glutarimide A mixture of 3-methyl-3-n-propyl-glutarimide (25 g, 0.15 mol) obtained according to N. s. Benica et al., 1,4-dibromobutane (33.5 g, 0.15 mol) and potassium carbonate (4.6 g, 0.29 mol) are stirred and boiled for 16 hours In 250 ml of acetonitrile. Insoluble materials are removed by filtration and the filtrate is concentrated in vacuo to an oil. Distillation of the residual oil gives 42.5 g (95%) of N- (4-bromobutyl) -3-methyl-3-n-propylglutarimide as a pale yellow oil, b.p. 165-190 ° / 0.09 mmHg.

(b) Hydrochloride of the title product By reacting N-30 (4-bromobutyl) -3-methyl-3-n-propylglutarimide with 3- (1-piperazinyl) -1,2-benzisothiazole and converting the free base to the hydrochloride salt according to the method of Example 3. 1- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -4-methyl-4-propyl-2,6-piperidinedione hydrochloride, m.p. 163-165 ° C.

28 78697

Analysis for C 24 H 34 N 4 O 2 S * HCl Calc'd: C 60/18 H 7.37 n 11.70 Found: C 60.13 H 7.46 N 11.52 NMR (CDCl 3): 0.91 (3H, t, 6, 0Hz), 1.01 (3H, s), δ 1.29 (2H, m), 1.68 (2H, q, 6.8Hz). 1.85 (4H, m), 2.53 (4H, s), 3.25 (6H, m), 3.79 (2H, t, 6.9Hz), 4.08 (4H, m), 7 , 41 (2H, m), 7.84 (2H, m), 12.70 (1h, bs).

Example 10 1- [4- / 5- (1,2-Benzisothiazol-3-yl) -1-piper-10-azinyl] butyl] -4,4-dimethyl-2,6-piperidinedione CH3 ° ch3 o \ s

A mixture of N- (4-bromobutyl) -3,3-dimethyl-20-liglutarimide (4 g, 0.0145 mol) obtained according to the method of Example 9, 3- (1-piperazinyl) -1, 2-benzisothiazole (3.18 g, 0.0145 mol), anhydrous potassium carbonate (20.04 g, 0.145 mol) and Kalim iodide (0.25 g, 0.0015 mol) in 150 ml of acetonitrile, stir and boil for 12 hours. The reaction mixture is filtered, evaporated to dryness in vacuo and the residue is triturated with ether. Crystallization of the solid thus obtained from ether gives, in 64% yield, analytically pure 1- [4 - [4- (1,2-benziso-30-thiazol-3-yl) -1-piperazinyl] butyl] -4,4-dimethyl- , 6-piperidinedione, m.p. 146-147 ° C.

Analysis for C 22 H 30 N 4 O 2 S: Calculated: C 63.74 H 7.29 N 13.52 Found: C 63.78 H 7.11 N 13.71 35 NMR (CDCl 3): 1.06 (6H, s), 1 , 56 (4H, m), 2.48 (4H, s), 2.60 (6H, m), 3.55 (4H, m), 3.80 (2H, t, 7.0Hz), 7, 38 (2H, m), 7.85 (2H, m).

29 7 3 6 9 7

Example 11 1- / 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -4,4-diethyl-2,6-piperidininedione CH3CH2 / O- (c, 2,4-Q, -10 CH 3 CH 2 O (a) N- (4-bromobutyl) -3,3-diethylglutarimide A solution of 3,3-diethylglutarimide (7.0 g, 0.041 mol) ) obtained by the method of NS Benica et al., supra, and sodium hydroxide (1.64 g, 0.041 mol) in 100 ml of 70% ethanol are heated and stirred for 20 minutes. The solid sodium salt of 3,3-diethylglutarimide, suspended in 150 ml of dimethylformamide and treated with 1,4-dibromobutane (17.7 g, 0.082 mol), is stirred at room temperature for 48 hours and then evaporated to dryness in vacuo. The residue was dissolved in chloroform, filtered, and the filtrate was concentrated and distilled to give 11.4 g (yield 93%) of N- (4-bromobutyl) -3,3-diethylglutarimide.

(b) Hydrochloride hydrate of the title product By reacting N- (4-bromobutyl-3,3-diethylglutarimide with 3- (1-piperazinyl) -1,2-benzisothiazole and converting the free base to the hydrochloride salt in isopropanol according to Example According to Method 3, (1,2-benzisothiazol-3-yl) -1-piperazinyl-4-butyl-4,4-diethyl-2,6-piperidinedione hydrochloride hydrate, mp 179-183 ° C, is obtained from acetonitrile. .

35 30 78697

Analysis for C 24 H 34 N 4 O 2 G-HCl-O / 25H 2 O: Calculated: C 59.61 H 7.40 n 11.59 Found: C 59.50 H 7.24 n 11.50 NMR (DMSO-d 6): 0.79 (6H, t, 7.5Hz), 1.32 (4H, q, 7.5Hz), 1.60 (4H, m), 2.55 (4H, s), 3.44 (10H, m) , 4.07 (2H, in), 7.52 (2H, in), 8.11 (2H, in), 11.78 (1H, bs).

Example 12 4- [N- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone

O

/ = \ i f ~ \. B-a-NCH - [N - N - [- (15-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane As described in Chem. Abs. 63, 9959b (1965), a mixture of 4-chloro-4'-fluoro-20-butyrophenone (20 g), ethylene glycol (6.9 g) and p-toluenesulphonic acid (0.05 g) in 50 ml of benzene, boil for 30 h, collecting off the water formed. Concentration of the reaction mixture in vacuo gives 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane.

25 (b) Hydrochloride of the title product A mixture of 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane (4.31 g, 0.0176 mol), 3- (1-piperazinyl ) -1,2-benzisothiazole (3.86 g, 0.0176 mol), ground potassium carbonate (2.43 g, 0.0176 mol) and potassium iodide (0.88 g, 0.0053 mol) in 180 ml in a dry acetone trill, boil for 20 hours. The reaction mixture is filtered, concentrated in vacuo and the residual oil is dissolved in chloroform and filtered. Concentration of the filtrate gives an oily residue which is dissolved in 35 ml of ethanol containing 10 ml of 3-norm. hydrochloric acid, 3i 78697 and boil for 15 minutes. Acetonitrile is added to the cooled mixture and the resulting solid is collected, 3.3 g, m.p. 248-250 ° C. Crystallization of this material from ethanol gives analytically pure 4- [4- (1,2-5 benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride, m.p. 251-254 ° C. Analysis for C 21 H 22 FN 3 OS'HCl! calculated: C 60.06 H 5.52 N 10.01 found: C 59.70 H 5.47 N 9.78 10 NMR (DMSO-d 6): 2.12 (2H, m), 3.25 (6H , m), 3.56) 4H, m), 4.06 (2H, d, 12.0Hz), 7.41 (4H, m), 8.08 (4H, m), 11.60 (1H, bs).

Example 13 - [4- [4- (1,2-Benzisothiazol-3-yl) -1-Piper-15-acyl] propyl] -4-fluorobenzenemethanol

OH

3 "C n

Sodium borohydride (1.0 g, 0.026 mol) is added portionwise to a stirred suspension of 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1- butanone hydrochloride (3.34 g, 0.008 mol) in 150 ml of absolute ethanol. The mixture is stirred for 20 hours, acidified with ethanolic hydrogen chloride solution, stirred for a further 2 hours, and concentrated in vacuo. The residue was partitioned between chloroform and 1N aqueous sodium hydroxide, and the chloroform phase was dried over magnesium sulfate and evaporated to dryness in vacuo to give 2.31 g (yield 69%) of the title compound as the free base. The free base is converted to the hydrochloride with an ethanolic solution of hydrogen chloride in ethanol to give O, N-3- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) -prop.

Pyl / “4 “fluorobenzenemethanol hydrochloride, m.p. 200-202 ° C.

Analysis for .HCl: Calculated: C 59.78 H 5.97 N 9.96 Found: C 59/34 H 5.95 N 9.82 NMR (DMSO-dc): 1.70 (4H, m), 3.40 (8H, m), 4.05 b (2H, d, 12.0 Hz), 4.59 (1H, m), 5.30 (1H, bs), 7.35 (6H, 10 m), 8.10 (2 H, m), 11.20 (1H, bs).

Example 14 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone

O

F-ac- (c ^ O t j0 20 °

By reacting 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane with 3- (1-piperazinyl) -1,2-benzisoxazole according to the method of Example 12 and converting the free base to the hydrochloride salt, 25% yield of 4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride, m.p. 260-262 ° C, from methanol (25% yield). Analysis for C 21 H 22 N 2 O 2 • HCl: Calculated: C 62.46 H 5.75 N 10.41 Found: C 62.18 H 5.59 N 10.50 NMR (DMSO-d 6): 2.11 (2H, m), 2.56 (2H, m), 3.40 (8H, m), 4.12 (2H, m), 7.33 (5H, m), 7.60 (1H) , m), 8.06 (2H, m), 11.20 (1H, bs).

35 33 78697

Example 15

Qb - [3- / 4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol

5 OH

4- [4- (CWCH2.3-) -N- [4- (4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone- reduction of the hydrochloride (2.0 g, 0.005 mol) with sodium borohydride (0.57 g, 0.015 mol) in 200 ml of absolute ethanol is carried out according to the procedure of Example 13. After concentrating the acidified mixture, the residue is basified with sodium hydroxide and extracted with chloroform. The combined extracts are dried over magnesium sulfate, concentrated in vacuo and triturated with ether to give 1.2 g of the free base product. Crystallization of this material from ethanol gives analytically pure (1,2-benzisoxazol-3-yl) -1-piperazinyl-4-propyl-14,7-4-fluorobenzenemethanol, m.p. 142.5-143.5 ° C.

Analysis for C 21 H 24 FN 3 O 2: Calculated: C 68.28 H 6.55 N 11.38 Found: C 68.13 H 6.56 N 11.43 NMR (CDCl 3): 1.79 (4H, m), 2 .60 (6H, m), 3.64 (4H, m), 4.68 (1H, m), 7.22 (8H, m).

30 35 34 78697

Example 16 8- [4- [5- (2,1-Benzisotlazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,7] decane-7,9-dione [N ., ^

_A_ ^ (2.4 \ _j rjY

10 N

(a) 3- (1-Piperazinyl) -2,1-benzisothiazole Sesota with 3-chloro-2,1-benzisothiazole (4.79 g, 0.028 mol), obtained from Albert et al., J. Het.

Chem., 15, 529 (1978), and piperazine (36.2 g, 0.42 mol) is heated at 120 ° C for 18 hours in a sealed reactor. The cooled reaction mixture is dissolved in 400 ml of water and the aqueous solution is extracted with ether and then with methylene chloride. The combined extracts are dried over magnesium sulphate and evaporated to dryness in vacuo to give 5.67 g (90%) of 3- (1-piperazinyl) -2,1-benzisothiazole as the free base.

A sample of the free base is converted to the hydrochloride salt in ethanol with an ethanolic solution of hydrogen chloride to give analytically pure 3- (1-piperazinyl) -2,1-benzisothiazole dihydrochloride, m.p. 274-276 ° C (dec.).

(b) Dihydrochloride dihydrate of the title product A mixture of 3- (1-piperazinyl) -2,1-benzisothiazole (4.0 g, 0.018 mol) and 8- (4-bromobutyl) -8-aza-spiro N, N-decane-7,9-dione (5.5 g, 0.018 mol), anhydrous potassium carbonate (4.98 g, 0.036 mol) and potassium iodide (0.83 g, 0.005 mol) in 100 ml of acetonitrile. stirr at reflux for 20 hours. The reaction mixture was filtered, evaporated to dryness in vacuo and the residue triturated with ether to give 7.38 g (93% yield) of the title product as the free base. Conversion of the free base to the hydrochloride salt in ethanol with ethanolic hydrogen chloride solution and crystallization from ethanol gives 5.34 g (57% yield) of analytically pure 8- (4-4-4- (2,1-benzisothiazol-3-yl) -1-piperazinyl). butyl 4-e-azaspiro [i], decane-7,9-dione dihydrochloride hemihydrate, m.p.

225-227 ° C (dec.).

Analysis for c 24 H 32 N 4 O 2 S.2HCl 1.0.5H 2 O: 10 Calculated: C 55.17 H 6.76 N 10.73 Found: C 55.55 H 6.84 N 10.97 NMR (DMSO-d 6): 1.52 ( 12H, m), 2.63 (4H, s), 3.57 (12H, m), 7.05 (1H, m), 7.46 (2H, m), 7.90 (1H, d, 8 (OH 2), 9.35 (2H, bs).

Example 17 8- [4- [4- (6-Chloro-1,2-benzisoxazol-3-yl) -1-piperazinyl] methyl] -5-azaspiroyl, 5'-decan-7,9-dione. 3 4 5 6 7 8 9 10 11 2 (a) 3- (1-Piperazinyl) -6-chloro-1,2-benzisoxazole A mixture of 3,6-dichloro-1,2-benzisoxazole 4 and piperazine, is reacted according to Method 5 of Example 2. The 3- (1-piperazinyl) -6-chloro-1,2-benzisoxazole-6-sol intermediate is isolated in 79% yield and used without further purification.

8 (b) The title product By giving 8- (4-bromobutyl) -9,8-azaspiro [4,5] decane-7,9-dione (2.03 g, 0.067 mol) 10 and 3- (1-piperazinyl) - React 6-1,2-benzisoxazole (1.6 g, 11.067 moles) according to the procedure of Example 3 to give crude base which is converted to the hydrochloride salt and crystallized from ethanol. The salt is dissolved in water and basified with ammonium hydroxide to give the free base which is crystallized from isopropanol to give 0.3 g (10% yield) of analytically pure 8- [4- [T- (6-chloro-1,2- benzisoxazol-3-yl) -1-piperazinyl / butyl] -8-azaspiro [4 (j) (decane-7,9-dione, mp 127.5-128.5 ° C).

Analysis for C 18 H 19 ClN 3 O 2: 24 31 43 10 Calculated: C 62.81 H 6.81 N 12.21 Found: C 62.73. H 6.83 N 12.35 NMR (DMSO-d 6): 1.48 (12H, m), 2.32 (2H, m), 2.60 (4H, s), 3.40 (10H, m) , 7.30 (1H, dd, 8.0, 1.8Hz), 7.74 (1H, d, 1.8Hz), 7.98 (1H, d, 8.0Hz).

Claims (15)

37 78697 A process for the preparation of therapeutically active compounds of the formula I R-N N — η- \ / Π 1 '-' n li Y z wherein R is a group of the formula 0 R 0 X N- (CH ~) - X N-ICHJ - L / νχ ./M. o o (a) (b) K | N- <CH2) n- N- (CH2> n “s— (s ~ V 0 0 (c) (d) 0 or OH C ~ (CH2) 3" fOch- (Cli2) 3 "(e) (f ) 38 78697 wherein n is 3 or 4, and R 2 are independently alkyl of 1 to 4 carbon atoms, 5. is oxygen or sulfur, Z is hydrogen or halogen, or pharmaceutically acceptable non-toxic acid addition salts thereof, known u about that Process according to Claim 1, characterized in that R is the 8-azaspiro [4,5] decane-7,9-dione radical (a). Process according to Claim 2, characterized in that 8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-aza-spiro] -decane- N-dione, 8- [4- (4- (4--benzisoxazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,5] decane-7,9-dione or 8- 4- (6-chloro-1,2-benzisoxazol-3-yl) -1-piperazinyl-7-butyl-7-8-azaspiro [4,5] decane-7,9-dione, or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that R is R 1, R 2 -glutarimide (b). Process according to Claim 4, characterized in that 1- [4- [4- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl} -4-methyl-3H-4-propyl 2,6-piperidinedione, 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -4,4-dimethyl-2,6-piperidinedione or 1- 4- [4- (1,2-benzisothiazol-43-78969 sol-3-yl) -1-piperazinyl] t-butyl] -4,4-diethyl-2,6-piperidinedione, or a pharmaceutically acceptable acid addition salt thereof. 5 wool Vlllb rt ° 10 / ° or p S—% B— \ 0 0 VIIIc VUId 15 in which and R2 are as defined above are reacted with a compound of formula IX H2N- (CH2) n-N N-r- | P> | IX Nx z 25 wherein n, Y and Z are as defined above, in an inert reaction solvent for a time sufficient to form a compound of formula I, or E) for the preparation of compounds of formula I wherein R is as defined above for formula (e) or a group according to (f), a compound of formula III 42 78697 wherein Y and Z are as defined above, is alkylated with a compound of formula X 5 ΓΛ / = \ J> x F ~ \ _y — c— <ch2> 3 ' x 10 wherein X is as defined above in an inert solvent to give a compound of formula I wherein R is a group of formula (e) and the resulting compound is reduced, if desired, to a compound of formula I wherein R is a group of formula 15 (f), and if desired, converting a compound of formula I obtained by Method A, B, C, D or E into a pharmaceutically acceptable non-toxic acid addition salt. Process according to Claim 1, characterized in that R is a 2,4-thiazolidinedione radical (c). Process according to Claim 6, characterized in that 3- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl} butyl] -7-2,4-thiazolidinedione or 3- [4- 4- [3- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -butyl] -2,4-thiazolidinedione, or a pharmaceutically acceptable acid addition salt thereof. Process according to Claim 1, characterized in that R is a spirocyclopentyl-2,4-thiazolidinedione radical (d). Process according to Claim 8, characterized in that 8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl] -6-thia-8-azaspiro [4.47] nonane-7 , 9-dione or 8- [4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] butyl] -6-thia-8-azaspiro [4.4] nonane-7,9- dione, or a pharmaceutically acceptable acid addition salt thereof. Process according to Claim 1, characterized in that R is a group of formula (e). A) for the preparation of compounds of formula I wherein R is a group of formula (a), (b), (c) or (d) as defined above, an imidoyl compound of formula II imide-A II wherein A is - (CH 2) ) nX, where n is as defined above and X is an acid residue of a reactive ester group, and the imide is a group of formula 20. R. DC- & O * 0 25 (a '> (b1) r <0 O- ^ 0 N- or N- S_ (C) (d ') wherein R 1 and R 2 are as defined above is reacted with a compound of formula III 39 73697 "& τΧΧ γ Ν / Ν ζ 5 wherein Υ and Ζ are as defined above, in an inert reaction in a medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or B) for the preparation of compounds of formula I wherein R is a group of formula (a), (b), (c) or (d) as defined above , an imidoyl compound of formula IV imide-M IV wherein M is an alkali metal salt and the imide is a group of formula (a1), (b *), (c ') or (d1) as defined above is reacted with a compound of formula V or V 20 / Λ ^ X- (CH) -NN r- wTAÄ 25 or * QCnttO. 30 z in which n, X, Y and Z are as defined above, in an inert reaction medium at a suitable temperature for a period of time sufficient to to form a compound or «73697 alternatively, without pre-forming an alkali metal of formula IV the free imide compound of formula (a '), (b1), (c') or (d *) is reacted with a compound of formula V or V in an inert reaction medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or C) for the preparation of compounds of formula I wherein R is a group of formula (a), (b), (c) or (d) as defined above, a compound of formula VI 10 imide- (CHO) 2 NH VI 2. wherein the imide is a group of formula (a ') / (b *), (c') or (d1) as defined above and n is as defined above, is reacted with a compound of formula VII. . ------ wherein halo is halogen and Y and Z are as defined above, in an inert reaction medium in the presence of a base at a suitable temperature for a time sufficient to form a compound of formula I, or D) to prepare compounds of formula I wherein R is as defined above a group according to a), (b), (c) or 30 (d), an anhydride of formula Villa, VIIIb, Ville or VHId «78697 d3:,> α: Process according to Claim 10, characterized in that 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone or 4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone or a pharmaceutically acceptable acid addition salt thereof. Process according to Claim 1, characterized in that R is a group of formula (f). 44 78697 Process according to Claim 12, characterized in that 3- [E] - [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol or C 1-4 [4- (1,2-benzisoxazol-5-yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol, or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the compound 8 - [4-, 4- (1,2-benzisothiazol-3-yl) -1-piperazin-10-yl] butyl] -8-azaspiro [4.5] decane-7,9- dione, characterized in that a mixture of 3- (1-piperazinyl) -1,2-benzisothiazole, 8- (4-bromobutyl) -8-azaspriro [4,4] decane-7,9-dione and base, is reacted in an inert reaction medium at a suitable temperature for a sufficiently long time 8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro / 4.0- to form decane-7,9-dione as the free base, and the free base is converted, if desired, to the hydrochloride salt or the dihydrochloride dihydrate salt. A process according to claim 1 for the compound 8- [4 - [. 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] t-butyl] -8-azaspiro [4.4] decane-7.9 -dione, characterized in that a mixture of 3- (1-piperazinyl) -1,2-benzisothiazole, 1,4-dibromo-25-butane and a base is reacted in an inert solvent at a suitable temperature to give 8- (1,2-Benzisothiazol-3-yl) -8-aza-5-azonia-spiro [1,5] decane bromide, which is further reacted with 3,3-tetramethyleneglutarimide in an inert solvent in the presence of a base for a sufficient time time to form 8- [4- / 4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4,0-decane-7,9-dione as the free base. 45 78697